Approximately 20% of the 2 million troops deployed to Iraq and Afghanistan may require treatment for post-traumatic stress disorder (PTSD). Bipolar disorder, a sequel to PTSD is common among Veterans. Currently about 30% of the bipolar Veterans receive chronic lithium (Li) therapy, which also effectively prevents suicidal tendencies. However, chronic usage of lithium is limited by the development of nephrogenic diabetes insipidus (NDI), a condition in which the kidneys cannot concentrate urine resulting in excessive loss of water and electrolytes. Currently used modalities for the treatment of NDI are encountered with varying degrees of success as well as side effects. Refinement and/or replacement of the current side effect-prone therapies with new drugs based on an improved understanding of molecular pathophysiology of Li-induced NDI should result in improved efficacy and fewer side effects. In this context, we discovered that a signaling system, called purinergic signaling, can be targeted to ameliorate Li-induced NDI. The goal of this project is to decipher the role of ADP-activated P2Y12 receptor (R) in Li- induced NDI. This will have significant impact on our current knowledge of pathophysiology of Li-induced NDI, with a potential for the development of novel therapies. We observed that P2Y12-R is expressed in the kidney, and its selective blockade by clopidogrel bisulfate (Plavix(r)), a widely used anti-clotting drug, increases the ability of the kidney to conserve water, and ameliorates Li-induced NDI. Based on these novel observations, we hypothesize that blockade of P2Y12-R ameliorates Li-induced NDI by re- sensitizing the kidney collecting duct to the action of AVP. We further hypothesize that P2Y12-R blockade suppresses Li-induced increases in prostanoid and nitric oxide production, and oxidative stress, thus contributing to overall beneficial effect. To address this hypothesis, we propose three specific aims, and use rat and mouse models, cultured kidney collecting duct cells, and agents that modulate signaling through for P2Y12R. Aim # 1 is to investigate the effect of P2Y12-R on Li-induced decrease in APQ2 expression in the collecting duct and the potential mechanisms involved in it. Aim # 2 is to investigate the beneficial effects of P2Y12-R blockade on Li-induced increases in prostanoid and nitric oxide production and oxidative stress. Aim # 3 is to evaluate the therapeutic benefits of targeting P2Y12-R (with or without concurrent blunting of P2Y2-R) on Li-induced NDI, collecting duct remodeling and cell proliferation in the kidney. Thus, this proposal is based on a novel concept, observations, and hypothesis, and it shifts the current focus of research and therapies for Li-induced NDI from predominantly the ones that counter anti- AVP effects to the ones that enhance the sensitivity of the kidney to AVP, thereby ensuing minimal side effects.